tbuckley/cabot-search huggingface dataset:
DDEL-15. METHOTREXATE AREA UNDER THE CURVE IN PRIMARY CNS LYMPHOMA
Authors: Dana Moussalli, Anh Huan Vo, Maria Turchan, Rochelle Fu, Prakash Ambady
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION There is consensus that high-dose methotrexate-based (HD-MTX) chemotherapy is the first line treatment for primary central nervous system lymphoma (PCNSL) but there is no consensus on drug dosing and duration. Area under the curve of Methotrexate (MTX-AUC) is a measure of exposure, and we hypothesize that a high MTX-AUC is associated with improved overall survival (OS) and progression free survival (PFS).Method: This retrospective study was approved by the institutional review board. HIV negative PCNSL patients who received Rituximab and HD-MTX at our institution from 2002-2020 were included. HD-MTX dose ranged from 1.2 gm/m2-8 gm/m2 based on creatinine clearance. MTX-AUC was calculated using mtxpk.org. OS and PFS were analyzed using Kaplan-Meier method and Cox proportional hazard regression. Result: 34 PCNSL patient’s charts (mean age: 67 yrs ± 15, 22F/12M) were reviewed. The mean MTX dose (5313 mg/m2) strongly correlated with the mean MTX-AUC (3648 μmol*l−1h, range: 698 – 6634). Patients with MTX-AUC &amp;lt; 3648 μmol*l−1h median PFS is 44.6 months (95% CI: 3.8– non-estimable), not significantly different from patient with MTX-AUC &amp;gt; 3648μmol*l−1h (PFS: 53.2 months, 95% CI: 4.3– non-estimable; P = 0.96). Results were similar after adjusting for patient characteristics in the Cox regression with hazard ratio (HR): 0.84; 95% CI: 0.29–2.43; P = 0.75). The median OS was 44.6 months (95% CI, 12.5– non-estimable) for patients with MTX AUC &amp;lt; 3648 μmol*l−1h and not estimable for patients with MTX-AUC &amp;gt; 3648 μmol*l−1h , HR of 0.43 (95% CI: 0.08–2.33; P = 0.33). Higher KPS prior to chemotherapy was associated with improved PFS/OS with HR: 0.95 (95% CI: 0.93–0.98; P = 0.0006) and HR: 0.91 (95% CI: 0.87–0.96; P = 0.0005) respectively. CONCLUSION Our patients PFS and OS is improved compared to historical control but our data suggests that there is no statistically significant association with MTX-AUC in PCNSL.
QOL-14. IDENTIFICATION OF CHALLENGES FACED BY CAREGIVERS OF PATIENTS WITH NEWLY DIAGNOSED GLIOMAS
Authors: Julia Gomez, Lauryn Hemminger, Sandhya Seshadri, Jennifer Serventi, Nimish Mohile, Benzi Kluger
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Describe the most common and challenging issues facing caregivers of patients with newly diagnosed gliomas. BACKGROUND Despite growing evidence that caregivers of brain cancer patients have high burden, there are no studies on what specific aspects of caregiving are most challenging. Understanding these specifics can inform better approaches to support them. METHODS Prospective study of caregivers of patients with newly diagnosed gliomas (glioblastomas, anaplastic astrocytomas, and low-grade gliomas). Caregivers (n=57 at baseline) used free-text fields to report the most challenging aspects of caregiving at baseline, 3 months, 6 months, and 12 months after diagnosis. Responses were grouped into categories for analyses and examined utilizing the Model to Guide Patient and Family Care. RESULTS Caregiver participants included spouses (n=34), children (n=12), and others (n=11) and the majority of tumors were high-grade gliomas. The most common challenges at each time point were coping with diagnosis and associated mortality and uncertainty (32% at baseline), providing hands-on care (27% at 3 months), dealing with the patient’s emotions (33% at 6 months), and providing hands-on care, witnessing cognitive/behavioral changes, and seeing physical deficits (each 30% at 12 months). Psychological challenges such as dealing with emotions, coping with the diagnosis, or witnessing cognitive/behavioral changes were common across all time points. Social challenges such as communication difficulties and shifting relationships and family dynamics were less common. At baseline, coping with the new diagnosis was most challenging for caregivers, whereas at 12-months, the patients’ cognitive, behavioral, emotional, and physical difficulties became more pronounced resulting in the need for more hands-on care. The data was limited by dropouts, particularly at 12-months(n=20). CONCLUSION Caregivers of glioma patients experience challenges that evolve in the 12 months following diagnosis. These results provide a starting point to better screen caregivers for distress and develop targeted interventions to improve caregivers’ quality of life.
CTNI-52. A RANDOMIZED CONTROLLED TRIAL OF BERUBICIN, A DOXORUBICIN ANALOG THAT EFFECTIVELY CROSSES THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS
Authors: Sandra Silberman, Sigmund Hsu, Don Picker, Zena Muzyczenko, Waldemar Priebe
Journal: Neuro-Oncology (2022)

Abstract Berubicin is a doxorubicin (Dox) analog that crosses the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%.A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and EU is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival and overall response rates. Advanced imaging technology is being utilized for consistency in the evaluation of MRI scans. An interim futility analysis to explore the relative efficacy of these drugs will be conducted after up to half of the patients enrolled have reached 6 months of therapy. Currently, 31 patients are enrolled with 21 in the Berubicin arm and 10 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 57% and 60% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 30% (Lomustine arm). Less than 10% of patients discontinued the study due to adverse events.The available data to date shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. This study is continuing to evaluate the efficacy of this novel drug with the goal of providing therapeutic options for patients after first-line therapy. An updated patient population profile, safety, and initial efficacy will be presented.
BIOM-21. THE EFFECTIVENESS OF CIRCULATING MICRO RNAS DERIVED FROM GLIOBLASTOMA AS A BIOMARKER FOR EARLY DIAGNOSIS AND PROGNOSIS
Authors: Hyun Joo Park, Kihwan Hwang, Ji-Eyon Kwon, Ji Yun Han, Kyoung Un Park, Yong-Kil Hong, Chae-Yong Kim
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma is the most common primary intracranial malignancy in adults. In cases where biopsy is not feasible due to tumors in inoperable locations including the brainstem, biomarkers such as micro RNA-21 (miR-21) extracted from blood samples could be utilized for diagnostic or prognostic purposes. In this study, we examined the role of miR-21 as a diagnostic factor in patients with glioblastoma. METHODS Inclusion criteria included patients with age greater than 20 years and with histologic confirmation of diagnosis. The blood samples were collected prior to surgery, after surgical resection, after concurrent chemoradiotherapy, and after 3 cycles of adjuvant temozolomide therapy. Using TaqMan assay, we extracted miR-21 from blood samples and compared its level with tumor volume on brain magnetic resonance imaging (MRI) scans. miR-21 levels before and after treatments were compared within each subject. RESULTS Eleven newly diagnosed glioblastoma patients were enrolled in this study, and final analyses were performed for eight patients with complete follow up serum samples. Two patients with stable disease after treatment displayed a decrease in miR-21 levels. Three out of four subjects with increase in miR-21 showed progressive disease on MRI scans. One patient with stable disease and an increased miR-21 level experienced postoperative intracranial hemorrhage and ischemic event. The two patients with unchanged miR-21 levels showed stable disease. CONCLUSION miR-21 levels were associated with progressive disease in glioblastoma patients. miR-21 has potential be utilized as a diagnostic marker in patients with glioblastoma, and further studies are needed to elucidate its role as a prognostic marker.
NIMG-71. REAL-WORLD ASSESSMENT OF IDH1 INHIBITOR IVOSIDENIB IN IDH MUTANT LOWER GRADE GLIOMAS – THE JOHNS HOPKINS EXPERIENCE
Authors: Sushant Puri, Jessica Shi, Lindsay Blair, Jaishri Blakeley, John Laterra, David Kamson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND As clinical trials are ongoing to establish the role of IDH inhibitors in the treatment of lower-grade gliomas, long-term data is not yet available. Hence, here we share our real-world experience with off-label ivosidenib. METHODS In this single-institution retrospective analysis, we included chemo/radiotherapy-naïve, gadolinium non-enhancing WHO Grade 2/3 IDH1-mutated astrocytomas (AS) and oligodendrogliomas (OG) that were treated with off-label ivosidenib for ≥ 5 months for active tumor growth. We performed semi-automated volumetric analyses on T2/FLAIR images in 3D Slicer v4.11. Annualized growth-rates before and on ivosidenib were calculated, and time to initial response (reduction in growth-rate), growth arrest (growth-rate ≤ 0cc/yr) and shrinkage in patients with confirmatory data available (≥ 1 confirmatory follow-up scan). Progression-free survival (PFS), at 6 and 12 months were assessed (progression defined as ≥ 40% volume increase per RANO 3D). RESULTS We studied 12 patients (2F, median age 46yrs [range 26-60], 8/4 AS/OG; 4 grade 3) with an average of 17.2 months (5-33) follow-up on ivosidenib. Eleven (92%) patients had confirmatory data. Response rate was 82% (9/11) with median time of 4.9 (3.5-6.3) months to initial response and 11.1 (4.1-21.4) months to growth arrest. Growth arrest occurred 3-folds faster in OG than in AS (4.2±0.8 vs.12.5±4.2 months, p=0.014). Mean best response was 11.4±12.8% volume reduction, after a median of 12.1±9.3 months on ivosidenib. Mean PFS was 24.4 months (CI95%18.8-29.9). PFS-6 and PFS-12 were 91%, and 88% (7/8), respectively. No major toxicity was noted. There were 3 discontinuations, two for radiographic progression, one for increased seizure frequency. CONCLUSIONS In this small cohort, ivosidenib was well-tolerated with a high response rate; however, responses took up to a year to become evident and seemingly faster in oligodendrogliomas. These data suggest that ivosidenib might require more than 5 months of commitment and volumetrics may help the detection of early response.
EXTH-22. TARGETING A NEWLY DISCOVERED IMMUNE CHECKPOINT, SIGLEC-15, INCREASES ONCOLYTIC EFFICACY OF ZIKA VIRUS (ZIKV) IN GLIOBLASTOMA (GBM)
Authors: Ashwani Kesarwani, Sachendra Singh Bais, Sharmila Nair, Amanda Andrade De Costa, Tong Hu, Pei-Yong Shi, Michael S Diamond, Milan G Chheda
Journal: Neuro-Oncology (2022)

Abstract We are developing ZIKV as a therapy for GBM. We previously demonstrated ZIKV specifically kills GBM stem cells. Using GL261 and CT2A mouse models, ZIKV induces a CD8+ T-cell mediated anti-tumor response and leads to 65% and 40% long term survivors, respectively (0%-untreated controls). ZIKV treatment significantly increases the number of myeloid cells in the tumor microenvironment (with about 10,000 infiltrating macrophages per ZIKV-treated brain, 1,000 cells per untreated brain). We hypothesized that by targeting a myeloid immune checkpoint, we would further enhance efficacy. Siglec-15 is a newly described myeloid checkpoint, and anti-siglec-15 antibody is currently in clinical trial for patients with advanced or metastatic solid tumors (NCT03665285). While there was no effect of anti-siglec-15 treatment alone, we observed increased efficacy when combined with ZIKV (cure rate: GL261-70%, CT2A-60% with ZIKV+anti-siglec-15 antibody; GL261-20%, CT2A-0% with anti-siglec-15 antibody alone; GL261-30%, CT2A-25% ZIKV alone; GL261-0%, CT2A-0% without treatment). Since recurrence is a major problem, we performed re-challenge experiments in cured mice at 6 months. Mice previously treated with anti-siglec-15 antibody and ZIKV had 70% long-term survival, compared to 30% of age matched untreated controls. This supports our earlier findings that an immunological response after ZIKV engenders long-term, tumor-specific, immune surveillance. Lastly, we used Siglec-15 knockout mice to confirm our observations. After treating Siglec-15 knockout mice bearing CT2A tumors with ZIKV, 70% animals were cured. There was no significant difference in survival between CT2A-bearing Siglec-15 knockout mice without ZIKV treatment compared to CT2A-bearing wild type hosts. Taken together, our work suggests targeting putative myeloid suppressor cells, combined with oncolytic ZIKV and its ensuing anti-cancer stem cell and activated CD8+ T-cell effects, may be an effective tool in neuro-oncology. Targeting Siglec-15 may also enhance other oncolytic or cytotoxic therapies.
EXTH-19. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Veronica Rendo, Eudocia Lee, Nicholas Khuu, Kristine Pelton, Emily Lapinskas, Patrick Y Wen, Keith Ligon, Rameen Beroukhim
Journal: Neuro-Oncology (2022)

Abstract Over 60% of glioblastomas retain wild-type p53, resulting in potential susceptibility to MDM2 inhibitors. These molecules disrupt the interaction between p53 and its negative regulator MDM2, allowing downstream pathway signaling and cell fate decisions including growth inhibition and death resulting from cellular stress. We have analyzed clinical samples from 10 patients newly diagnosed with glioblastoma multiforme (GBM) and treated with the MDM2 inhibitor KRT-232. We detected upregulation of CDKN1A transcript (a target of p53) in all p53 wild-type tumors (8 of 10), but not in p53-mutant tumors (2 of 10). In patient-derived cell lines, treatment with KRT-232 at the clinically detected concentration was only sufficient to stall tumor growth. Cell death via apoptosis can be achieved when MDM2 inhibition is combined with the chemotherapeutic agent temozolomide. As the effects and resistance mechanisms of MDM2 inhibition remain poorly understood in GBM, we have additionally performed genomic and transcriptomic analyses in patient-derived cell lines to better characterize sensitive tumors and identify putative biomarkers of drug response. Dose response curves and growth assays showed that tumors with inactivating p53 mutations are highly resistant to treatment, but those that retain wild-type p53 exhibit various degrees of drug sensitivity. This suggests that other factors, in addition to p53 mutational status, mediate response to MDM2 inhibition in gliomas. Transcriptional analyses of patient samples following drug treatment suggest that cell division, chromatin reorganization, cell differentiation state and immune response programs become deregulated under MDM2 inhibition and in the absence of p53-inactivating mutations.
NIMG-11. THE EXTENT OF NECROSIS IN BRAIN METASTASES MAY PREDICT SUBTYPES OF PRIMARY CANCER AND OVERALL SURVIVAL IN PATIENTS RECEIVING CRANIOTOMY
Authors: Jihwan Yoo, Yoon Jin Cha, Sung Jun Ahn, Hun Ho Park
Journal: Neuro-Oncology (2022)

Abstract Although necrosis is common in brain metastasis (BM), its biological and clinical significances remain unknown. We evaluated necrosis extent differences by primary cancer subtype and correlated BM necrosis to overall survival post craniotomy. We analyzed 145 BM patients receiving craniotomy. Necrosis to tumor ratio (NTR) was measured. Patients were divided into two groups by NTR: BMs with sparse necrosis and with abundant necrosis. Clinical features were compared. To investigate factor relevance for BM necrosis, multivariate logistic regression, random forests, and gradient boosting machine analyses were performed. Kaplan–Meier analysis and log-rank tests were performed to evaluate the effect of BM necrosis on overall survival. Lung cancer was a more common origin for BMs with abundant necrosis (42/72, 58.33%) versus sparse necrosis (23/73, 31.51%, p&amp;lt; 0.01). Primary cancer subtype and tumor volume were the most relevant factors for BM necrosis (p&amp;lt; 0.01). BMs harboring moderately abundant necrosis showed longer survival, versus sparse or highly abundant necrosis (p=0.03). Lung cancer BM may carry larger necrosis than BMs from other cancers. Further, moderately abundant necrosis in BM may predict a good prognosis post craniotomy.
PATH-10. A CASE OF ADULT THALAMIC DIFFUSE MIDLINE GLIOMA, H3 K27-ALTERED WITH AN IMPRESSIVE RESPONSE TO RADIOTHERAPY AND CONCOMITANT PLUS ADJUVANT TEMOZOLOMIDE
Authors: Julien Rousseau, Moujahed Labidi, Jean-Paul Bahary, Karl Bélanger, France Berthelet, Sarah Lapointe
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG), H3 K27-altered is a newly defined diagnosis in the 2021 WHO Classification of Tumors of the Central Nervous System. H3 K27 alterations are associated with a uniformly poor prognosis in children with DMG, but they have been linked to improved survival in adults. Clinical experience in adults with DMG, H3 K27M-altered remains limited. Consequently, there exists a knowledge gap regarding the optimal management and responsiveness to chemoradiation therapy, which translates into the current absence of standard treatment. Here we present the case of an 18-year-old female patient treated for a thalamic DMG, H3 K27-altered at a Canadian tertiary center. The patient first presented with headache, dysarthria, and signs of increased intracranial pressure. Her initial brain magnetic resonance imaging demonstrated a right thalamo-mesencephalic lesion with central nodular enhancement and secondary hydrocephalus. She underwent an endoscopic third ventriculostomy followed by a subtotal resection, and pathology confirmed the presence of a DMG, H3 K27-altered, WHO grade 4. She was treated with combined radiotherapy and concomitant plus adjuvant (12 cycles) temozolomide. The Stupp regimen induced a spectacular response with a reduction in tumor dimensions on T2/FLAIR (20 x 18 mm versus 60 x 51 mm), &amp;gt; 50% decrease in size of the enhancing component, complete resolution of mass effect, and return to functional independence (KPS = 100%). Unfortunately, her disease progressed 16 months after diagnosis and she passed away 8 months later, despite having received 3 cycles of ONC201 through a clinical trial. Her progression-free survival (16 months) was superior to that reported in the literature, which could be related to her young age, subtotal resection status, and thalamic location. Although the addition of chemotherapy to adjuvant radiotherapy has not been shown to improve survival in children with DMG, the Stupp regimen may provide a survival benefit in adults.
BIOM-13. MICROPERFUSION-MEDIATED SOLUBLE EXTRACELLULAR ENVIRONMENT ANALYSIS FOR DETERMINATION OF CHEMOTHERAPEUTIC EFFICACY IN BRAIN TUMORS
Authors: Ian Olson, Andrew Zolp, Divya Ventarapragada, Jason Miska, Atique Ahmed
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most prevalent and lethally recurrent central nervous system neoplasm, but its therapeutic advancement has stagnated for over 15 years. One major hurdle in front of clinical breakthroughs has been the relative lack of real-time, treatment-responsive biomarkers that occur during therapy. The methods of microdialysis and microperfusion, now entering both clinical and pre-clinical settings, offers an opportunity to overcome this hurdle by providing real-time, biologically relevant monitoring of the tumor microenvironment (TME). The goal of this project is to identify changes in the soluble extra-cellular regional environment of the tumor (SECRETome) of GBM in response to standard-of-care treatments using intra-tumoral microperfusion. In this study, we evaluated the response of murine GBM tumors to temozolomide (TMZ) during therapy by combining transcriptional changes to metabolic phenotypes obtained from SECRETome analysis. Our data demonstrated a 2-fold increase in levels of microperfusion-sampled 2-hydroxyglutarate (2-HG) on day 3 post-TMZ therapy as compared to untreated tumors. This expression is correlated with our RNAseq analysis wherein we observed an &amp;gt;600 fold increase in malate dehydrogenase 1 (MDH1 - an enzyme that converts alpha-ketoglutarate to 2-HG) on Day 4 post-TMZ treatment (p = 4.20e-04) as compared to untreated tumors. Therefore, we found that interstitial elevation of a TMZ-associated metabolite can be used to probe the genetic changes that occur within GBM during therapy. This proof-of-concept study demonstrates that microperfusion-mediated TME sampling can be used to understand the complex biological responses process that occurs during GBM chemotherapy, and may provide unique insights into how to better treat these tumors in the future. Moreover, the future establishment of clinical intra-operative microdialysis/microperfusion can be extrapolated to improve the pace of clinical therapeutic translation through homologous, treatment-responsive biomarkers in humans.
CTNI-32. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: ZhongPing Chen, Chengcheng Guo, JianGen Chen
Journal: Neuro-Oncology (2022)

Abstract VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.